Canadian Journal of Physiology and Pharmacology Hypersensitivity reactions to LMWHs: different patterns of cross-reactivity in three patients. Case series and a literature review. Journal: Canadian Journal of Physiology and Pharmacology Manuscript ID cjpp-2017-0246.R1 Manuscript Type: Brief Report Date Submitted by the Author: 17-Jul-2017 Complete List of Authors: Juricic Nahal, Danica; University Hospital Centre Zagreb, Division of Clinical Pharmacology;Draft Agency for Medicinal Products and Medical Devices of Croatia Cegec, Ivana; University Hospital Centre Zagreb, Division of Clinical Pharmacology Erdeljic Turk, Viktorija; University Hospital Centre Zagreb, Division of Clinical Pharmacology Makar Ausperger, Ksenija; University Hospital Centre Zagreb, Division of Clinical Pharmacology Kraljickovic, Iva; University Hospital Centre Zagreb, Division of Clinical Pharmacology Simic, Iveta; University Hospital Centre Zagreb, Division of Clinical Pharmacology; University of Zagreb School of Medicine Is the invited manuscript for consideration in a Special N/A Issue?: cross-reactivity, delayed-type hypersensitivity reactions (DHR), immediate- Keyword: type hypersensitivity reactions (IHR), low molecular weight heparins (LMWH), skin tests https://mc06.manuscriptcentral.com/cjpp-pubs Page 1 of 12 Canadian Journal of Physiology and Pharmacology Hypersensitivity reactions to LMWHs: different patterns of cross-reactivity in three patients. Case series and a literature review. Short title: Hypersensitivity reactions to LMWHs Danica Juricic Nahal MD 1,3 *, Ivana Cegec MD 1, Viktorija Erdeljic Turk MD, PhD 1, Ksenija Makar Ausperger MD, PhD 1, Iva Kraljickovic MD, Iveta Simic MD, PhD 1,2 1 Division of Clinical Pharmacology, Department of Internal Medicine, University Hospital Centre Zagreb, Zagreb, Croatia 2 University of Zagreb School of Medicine, Zagreb, Croatia 3 Agency for Medicinal Products and Medical Devices of Croatia * Corresponding author: Danica Juricic Nahal MD Division of Clinical Pharmacology, Department of Internal Medicine, University Hospital Centre Zagreb, Kispaticeva 12, 10000 Zagreb, Croatia and Agency for Medicinal Products and Medical Devices of Croatia, Ksaverska cesta 4, 10000 Zagreb, Croatia Email: [email protected] Ivana Cegec MD Division of Clinical Pharmacology, DepartmentDraft of Internal Medicine, University Hospital Centre Zagreb, Kispaticeva 12, 10000 Zagreb, Croatia Email: [email protected] Viktorija Erdeljic Turk MD, PhD Division of Clinical Pharmacology, Department of Internal Medicine, University Hospital Centre Zagreb, Kispaticeva 12, 10000 Zagreb, Croatia Email: [email protected] Ksenija Makar Ausperger MD, PhD Division of Clinical Pharmacology, Department of Internal Medicine, University Hospital Centre Zagreb, Kispaticeva 12, 10000 Zagreb, Croatia Email: [email protected] Iva Kraljickovic MD Division of Clinical Pharmacology, Department of Internal Medicine, University Hospital Centre Zagreb, Kispaticeva 12, 10000 Zagreb, Croatia Email: [email protected] Iveta Simic MD, PhD Division of Clinical Pharmacology, Department of Internal Medicine, University Hospital Centre Zagreb, Kispaticeva 12, 10000 Zagreb, Croatia and University of Zagreb School of Medicine, Salata 3, 10000 Zagreb, Croatia Email: [email protected] https://mc06.manuscriptcentral.com/cjpp-pubs Canadian Journal of Physiology and Pharmacology Page 2 of 12 Abstract Low molecular weight heparins (LMWH) are used for a variety of indications. The most common type of hypersensitivity reactions to LMWHs are delayed-type hypersensitivity reactions (DHR). Immediate-type hypersensitivity reactions (IHR) occur only sporadically. Cross-reactivity of different LMWHs is a common and unpredictable problem. We present two cases of patients who developed DHR to nadroparin and enoxaparin, respectively. The third case presents a patient who developed IHR to nadroparin. Skin tests confirmed the hypersensitivity in all cases. In the cases of DHR, a skin test negative LMWH was identified and was tolerated in a challenge test. In the IHR case, cross- reactivity to all tested LMWHs was established. We hypothesize that the degree of cross-reactivity might depend on the type of hypersensitivity reaction with immediate reactions linked to more extensive cross-reactivity than delayed reactions. This is important to consider since, at least in some cases, a safe alternative LMWH can be identified. KEYWORDS: Cross-reactivity, Delayed-type hypersensitivity reactions (DHR), Immediate-type hypersensitivity reactions (IHR), Low molecular weight heparins (LMWH), Skin tests Draft https://mc06.manuscriptcentral.com/cjpp-pubs Page 3 of 12 Canadian Journal of Physiology and Pharmacology Manuscript text Introduction Low molecular weight heparins (LMWH) are used daily for a variety of indications. Although considered safe medications, hypersensitivity reaction can occur. The most common type of hypersensitivity reactions to LMWHs are delayed-type hypersensitivity reactions (DHR) which are reported in up to 10% of patients (Schindewolf et al. 2009; Schindewolf et al. 2013). Clinical manifestations of DHR include erythematous plaques and maculopapular exanthemas at the injection site. Immediate-type hypersensitivity reactions (IHR) to LMWHs are extremely rare and are limited to case reports (Gonzalez-Delgado and Fernandez 2016; MacLaughlin et al. 2002; Anders and Trautmann 2013; Leguísamo et al. 2015). Clinical manifestations of IHR include urticaria, hypotension, angioedema, pruritus and anaphylaxis. Skin tests including prick and intradermal test followed by a subcutaneous challenge test have been performed to establish the diagnosis of hypersensitivity to LMWHs and are generally recommended (Bircher et al. 2006; Brockow et al. 2013). Testing is contraindicated in cases of heparin induced thrombocytopenia (HIT). The problem of cross-reactivity among different LMWHs has been widely recognised and is reported in the literature in up to 89.7% of patients (Weberschock et al. 2011; Grassegger et al. 2001). Identification of a subset of patients who can tolerate an alternative LMWH after a hypersensitivity reaction to a Draftsingle LMWH would be of great clinical value. However, literature on such successful identifications is limited. Methods Skin test procedures at our Department are based on European Network for Drug Allergy (ENDA) publications (Brockow et al. 2002; Brockow et al. 2013). Prick tests are performed using undiluted commercially available LMWH preparations. Histamine is used as a positive, and 0.9% saline as a negative control. Readings are done after 10 minutes for histamine and after 20 minutes for tested LMWHs. Following negative results, intradermal tests are performed with LMWHs diluted to 1:10. Readings are done after 20 minutes (immediate reading) and on days 2, 3 and 7 (delayed readings). Immediate readings are considered positive if the size of the initial wheal increases by at least 3 mm in diameter after 20 minutes. Delayed readings are considered positive if the presence of infiltrated erythema is observed. After the completion of skin tests, a skin-test negative preparation is chosen for the subcutaneous challenge test. Undiluted LMWH is injected subcutaneously in the lower abdominal area with readings after 20 minute (immediate) and on days 2, 3 and 7 (delayed readings). Results (Case reports) Case No 1 presents a 40-year old female patient with a history of previous exposure to LMWH who developed generalised erythematous itchy plaques in 2015 after the administration of nadroparin prophylactically following knee surgery. The reaction developed after 2 days of nadroparin administration, but the exact time elapsed from the last nadroparin injection to the development of the cutaneous reaction could not be established. She was evaluated at our Department in June 2016. After obtaining a written consent, skin tests to dalteparin, nadroparin and enoxaparin were performed. Following negative prick tests to all tested heparins, intradermal tests (ID) were https://mc06.manuscriptcentral.com/cjpp-pubs Canadian Journal of Physiology and Pharmacology Page 4 of 12 performed and immediate readings were positive to nadroparin and dalteparin. Since ID tests to enoxaparin were negative, a subcutaneous challenge test with enoxaparin (1000 IU, 0.1ml) with immediate and delayed readings on days 0, 2, 3 and 7 was performed. All delayed readings were negative. Enoxaparin was well tolerated and provoked neither an immediate nor a delayed skin reaction. The patient was provided with written advice to avoid nadroparin and dalteparin while enoxaparin can be used as indicated. Case No 2 presents a 43-year old female patient who developed a skin reaction (without additional details provided) after 7 days of prophylactic treatment with enoxaparin due to a history of several miscarriages in June 2015. The exact time elapsed from the seventh injection of enoxaparin to the onset of the skin reaction could not be established. After the onset of the reaction the patient was switched to nadroparin. Nadroparin was administered for 2 days but was discontinued due to the persistence of the skin reaction. Further use of LMWHs was not deemed necessary since the patient experienced another miscarriage while on LMWH therapy. She was evaluated at our Department in September 2015. After obtaining a written consent, skin tests to dalteparin, nadroparin and enoxaparin were performed. Following negative prick test, ID test were performed. Immediate readings were negative